Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects 5 million Americans age 65 and older, and this prevalance is expected to increase more than 50% by the year 2030. AD, therefore, is a serious and growing challenge to the health and well-being of Americans, and research must be devoted to lessening its impact. An emerging potential therapy for Alzheimer's Disease (AD) is the transplantation of stem cells, and recently our laboratory has found that implanting neural stem cells (NSC) into the hippocampus of mice with the hallmarl<pathological features of AD reverses these animals'cognitive deficits. Remarkably, these cells seem to have no effect on the pathological features of AD, and instead seem to be influencing host cells to compensate for the detriment caused by the pathology. Before this stem cell-based approach can be implemented in AD patients, it is important to understand precisely how these influences on host cells are mediated. In addition, a detailed understanding of this restorative mechanism may facilitate refinement of the technique or direct the development of novel pharmacological approaches. There is compelling evidence that brain-derived neurotrophic factor (BDNF), a protein that is critical for memory-associated synaptic remodeling, is an important component ofthe mechanism by which NSCs restore cognition in mice with AD pathology. The current project will investigate the role of BDNF in the NSC-mediated restoration of cognition. Necessity will be determined by decreasing hippocampal BDNF levels by transplanting NSCs that have BDNF knocked-down or knocked-out. In addition, this project will examine the long-term efficacy of NSC transplantation, and whether efficacy can be improved by engineering NSCs to express an AD pathology-reducing enzyme, neprilysin. Recent stem cell-based approaches to treating Alzheimer's disease have been shown to reverse memory loss in animal models.. This project will investigate the critical role of a specific growth factor, brain-derived neurotrophic factor (BDNF), and an Alzheimer's pathology-reducing enzyme, neprilysin, in carrying out this stem cell-mediated reversal. A better understanding of BDNF and neprilysin in stem cells will help to improve stem cell-based therapies or direct drug development that reduces the impact of this devastating disease.